ABSTRACT The lymphatic system is essential in mediating tissue fluid homeostasis and intestinal lipid uptake. Importantly, lymphatic dysfunction positively correlates with body-mass index in morbidly obese patients accentuating the importance of the lymphatic system in maintaining metabolic homeostasis. In support, mice lacking one allele of Prox1 (a master regulator of lymphatic differentiation) develop adult onset obesity due to defective lymphatic vessels. How dysfunctional lymphatics aggravates metabolic syndrome, and conversely, how obesity impairs lymphatic function are poorly understood but highly medical relevant questions. This is highlighted by the fact that obese breast cancer patients undergoing lymphadenectomy are 3.6 times more prone to develop secondary lymphedema than non-obese breast cancer patients. Our long-term goal is to uncover molecular mechanisms governing lymphatic vascular function in health and disease and to identify critical regulators in hopes of offering potential new therapeutic targets to combat devastating metabolic disorders. We have identified two molecules that cooperatively regulate the pro-lymphangiogenic VEGFR3 signaling pathway. Using novel mouse models, we will determine whether manipulating these molecules will enhance the repair and regenerative response of lymphatic vessels after challenges such as lymphadenectomy and high fat diet. We will use sensitive imaging approaches and clinically relevant mouse models to address our questions. Specifically, we will determine molecular mechanism by which Foxc2 regulates lymphatic function in adult mice and define the regulatory machinery controlling the expression of Foxc2 and epsin in lymphatic endothelial cells. Finally, we will test the therapeutic potential of targeting Foxc2 or epsin in lymphatic dysfunctions. In summary, our findings could translate into innovative approaches to treat lymphatic dysfunctions and metabolic disorders.